Blood-brain barrier traversal by African trypanosomes

Johns Hopkins University, Baltimore MD

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Abstract

DESCRIPTION: (provided by the applicant): The neurological symptoms of sleeping sickness in man caused by Trypanosoma brucei gambiense and T b. rhodesiense are attributed to the penetration of the central nervous system by trypanosomes. Yet, how African trypanosomes cross the blood-brain barrier (BBB) remains an unresolved issue. Using an in vitro BBB system constructed of human brain microvascular cells (BMEC) we have initiated studies aimed at deciphering the mechanisms used by African trypanosomes to cross the BBB. Preliminary studies show that a human infective T. b. gambiense bloodstream form parasite isolate crossed the in vitro BBB model more efficiently than animal infective T. b. brucei 427. The parasites appeared to bind to intercellular junctions between BMEC. Equally motile procyclic forms do not bind or nor do they cross the barrier. More importantly, the BBB tight junctions remain intact, a finding that has been previously described in vivo. Inhibition of parasite BBI3 crossing by protease inhibitors suggests that parasite proteases play a role in BBB penetration. Our in Vitro model of the human BBB will be an important tool for understanding how African trypanosomes cross the BBB. The overall aims of this study will be to examine the in vitro potential of African trypanosomes to transverse the host blood-brain barrier and to dissect the underlying mechanism(s). We will characterize the kinetics of the interaction and traversal of Trypanosoma brucei spp. across an in vitro model of BBB. We will identify the mode of traversal of the barrier; e.g. paracellular or transcellular as well as examine the underlying mechanism(s) of the parasite and BMEC interactions. The results obtained from the proposed study will be a major step in our understanding of the initial events of African trypanosome invasion into the brain. Armed with this knowledge we will be better able to design therapies that will stop the parasites from entering the brain and prevent many of the agonizing neurological symptoms, which eventually lead to death.